1. Field of the Invention
The present invention relates to a process for the preparation of 2-methyl-1,3-dicarboxylates.
2. Discussion of the Background
2-Methyl-1,3-dicarboxylates of formula I 
in which R1 and R2 independently of one another represent an alkyl, aralkyl, aryl or cycloalkyl group or are a common part of a hydrocarbon chain and, in particular, diethyl 2-methyl-1,3-dicarboxylate, are of great interest as organic intermediates in the preparation of pharmaceutically active ingredients or crop-protection compositions.
Methylation processes for the preparation of a compound of formula I described in the literature usually start from the corresponding unsubstituted 1,3-dicarboxylate of the formula 
where R1 and R2 are defined as above. During methylation using usual alkylating agents, such as dimethyl sulfate or methyl bromide, mixtures of monomethylated products, dimethylated products and the unsubstituted starting materials are usually produced, which can only be removed by distillation with great difficulty.
A method which is better suited for obtaining pure monomethyl compounds of formula I involves reductive alkylation of the compounds of formula II by reaction with formaldehyde under hydrogenating conditions.
As described in DE-A-33 26 635, the disclosure of which is incorporated herein, very specific reaction conditions must be maintained in order to achieve relatively high conversions. Specifically, a process is described wherein a compound of formula II to be methylated is added to the mixture of the other reactants at an elevated temperature in the presence of both a Knoevenagel catalyst and a hydrogenation catalyst.
However, when a conventional amount of formaldehyde and solvent is used, quantitative conversion of the starting compounds of formula II is not achieved. The compounds of formula I prepared in this way can comprise from 0.5 to 2% of unreacted starting material, depending on the reaction conditions and the separation conditions chosen for the isolation of distillative product. In view of the fact that the compounds of formula I are used as intermediates for pharmaceuticals or crop-protection compositions, this result is completely unacceptable.
Accordingly, there is a need for a process for the preparation of compounds of formula I from the corresponding unsubstituted 1,3-dicarboxylates which produces the target products in high yields and with minimal content of unmethylated starting material.
It is an object of the invention to provide a process for preparing a 2-methyl-1,3-dicarboxylate in high yields with minimal production of by-products.
This and other objects of the invention have been achieved by reaction of a 1,3-dicarboxylate of formula II with formaldehyde and hydrogen, using, based on 1.0 mole of the dicarboxylate, from about 1.0 to about 2.0 mol of formaldehyde, and subjecting the reaction mixture or compounds isolated therefrom to thermolysis at a temperature of from about 50xc2x0 C. to about 300xc2x0 C.
In the process according to the invention, a catalyst combination is used comprising a hydrogenation catalyst and a Knoevenagel catalyst. The Knoevenagel catalyst used in the reaction may be acidic or basic in character. Typical catalysts of this type are, for example, pyridine and/or aliphatic amines.
Hydrogenation catalysts which may be used include, for example, Raney nickel or precious metals such as palladium, platinum or rhodium in pure form or in combined compositions, preferably on support materials. Suitable supports include, for example, activated carbon or aluminum oxide. Preference is given to palladium on activated carbon.
Suitable starting materials for use in the process of the invention include compounds of formula II where R1 and R2 may be selected from optionally substituted straight chain or branched alkyl groups of about 1 to 12 carbon atoms, optionally substituted aralkyl groups containing up to about 12 carbon atoms (e.g., benzyl, phenethyl or the like), optionally substituted aryl groups containing up to about 12 carbon atoms (e.g., benzene, naphthalene), optionally substituted cycloalkyl groups of up to about 12 carbon atoms (e.g., cyclopentyl, cyclohexyl) and compounds where R1 and R2 together form a saturated or unsaturated hydrocarbon chain of up to about 12 carbon atoms (e.g., butylene, hexylene). Suitable optional substituents include halogen (e.g., chloro or bromo) lower alkyl, alkoxy, amino, etc.
With regard to the prior art process in DE-A-33 26 635, it has been observed that the yield of compounds of formula I drastically decreased with increased amounts of formaldehyde, based on the amount of the compound of formula II used, while the formation of 2-hydroxymethyl-2-methyl-1,3-dicarboxylates of formula III increased. 
Thus, the by-product obtained in DE-A-33 26 635 during the reductive alkylation of diethyl malonate with formaldehyde and hydrogen is diethyl 2-hydroxymethyl-2-methylmalonate.
Further yield losses may result from ester condensation involving the hydroxymethyl group of the compound of formula III and may be observed in particular at temperatures greater than 100xc2x0 C., which are desirable for the purpose of achieving high space-time yields. This also is a limitation with respect to conditions for distillative separation of compounds of general formula I from compounds of formula III formed as by-product. A further limitation may arise from the observation that during the distillation of mixtures of the compounds of formula I and compounds of formula III at industrially significant temperatures of greater than 50xc2x0 C., decomposition reactions may cause formaldehyde to be liberated. In addition to contamination of the product, this can lead to deposits and, in the worst case, blockages in parts of the plant.
Surprisingly, it has been discovered that the amount of formaldehyde required to achieve a virtually quantitative conversion of the compounds of formula II without yield losses can be employed if the reaction mixture is subsequently subjected to thermolysis at from about 50xc2x0 C. to about 300xc2x0 C., preferably from about 100xc2x0 C. to about 200xc2x0 C., most preferably from about 130xc2x0 C. to about 170xc2x0 C.
It is possible to isolate the compounds of formula III formed under the preferred reaction conditions of reductive alkylation, and to subject them separately to thermolysis. In such cases, it has proven advantageous to employ a solvent which does not appreciably react with other components of the reaction mixture under the reaction conditions. Suitable solvents are: optionally halogenated aromatic or aliphatic hydrocarbons, alkanols (where R1=R2 ideally R1OH, since this avoids the formation of mixed malonates), carboxylic acids, ethers, cyclic ethers and polyethers such as diethylene glycol diethyl ether. Ethanol or acetic acid is particularly suitable. Solvent mixtures are also possible. The solvent should, however, have adequate dissolving power for water since water formed during the reaction may lead to problems with the hydrogenation catalyst.
With the aim of minimizing the process steps, the process is advantageously carried out by using the same solvent or solvent mixture for the thermolysis step, as used for the reaction of the compounds of formula II with formaldehyde and hydrogen. In a particularly advantageous manner, it is possible to dispense with separation and separate thermolysis of the compounds of formula III. For this, the reaction mixture, which comprises the compounds of formulae I and III, the solvent, the hydrogenation catalyst and the Knoevenagel catalyst, may be subjected to thermolysis without further work-up or following simple removal of the usually solid hydrogenation catalyst.
During the thermolysis procedure, the formaldehyde/solvent mixture should be maintained in order to avoid p-formaldehyde formation which could obstruct the apparatus. The mixture could be used subsequently in a synthesis. For example, an ethanol/formaldehyde mixture could be employed in the synthesis of 2-methylmalonic acid diethyl ester and 2-hydroxymethyl-2-methylmalonic acid diethyl ester.
A prerequisite for successful recycling of the solvent or solvent mixture is always that the water formed during the reductive alkylation is at least partly removed prior to thermolysis or at least partial dewatering of the solvent or solvent mixture takes place prior to its reuse. Preferred solvents or solvent mixtures for the thermolysis step are those which can be easily freed of water.
The selectivity of the thermolysis reaction, i.e. the formation of 2-methyl-1,3-dicarboxylates at the expense of oligomers and polymers, and the reaction rate can be improved by adding suitable catalysts. Such catalysts include alkali metal salts such as potassium acetate and copper-containing catalysts such as copper salts, in particular copper(II) acetate, which are homogeneously dissolved in the reaction mixture. Fixed-bed catalysts can also be used. These are easier to handle and separate. Examples include aluminum oxides or catalysts such as copper-containing ones, fixed to a support material.
Catalyst amounts of from about 0.01 to about 50.0 g, preferably from about 0.05 g to about 5.0 g, per mole of compound of formula II usually suffice. Particular preference is given to amounts of about 0.1 to about 2.0 g, and most preferable from about 0.5 g to about 1.6 g of catalyst per mole of the compound of formula II.
When copper (II) acetate is used as the thermolysis catalyst, it is advantageous to add the catalyst in portions or continuously. If the catalyst has been added to the reaction mixture for the reductive alkylation, and, to increase the solubility of the catalyst, an acid such as acetic acid also has been added, the thermolysis yields decrease markedly if the reaction mixture is stored for a period of several hours.
Since the thermolysis reaction proceeds very quickly in the presence of catalysts and in particular at temperatures of greater than 80xc2x0 C., the process according to the invention is advantageously carried out continuously. For this purpose, one can use, for example, a two-stage battery of stirred-tank reactors instead of a single reactor. However, the use of a falling-film, thin-layer or short-path evaporator as a thermolysis reactor has proven more favorable.
In addition to the advantage of a continuous and thus economical operation, one skilled in the art may also use mild reaction conditions, which effect rapid removal of 2-methyl-1,3-dicarboxylate from the reaction zone and thus minimize by-product formation. At the same time, the reverse reaction of compounds of formula I with liberated formaldehyde is suppressed.
In order to achieve rapid evaporation of the compounds of formula I, a vacuum is usually applied to the evaporator. The thermolysis is preferably carried out under a reduced pressure of from about 5 mbar to about 900 mbar, preferably from about 100 mbar to about 300 mbar.
Excellent yields and product purities are obtained when the compound of formula III or mixtures comprising the compound of formula III are added while distilling off the compound of formula I continuously into a hot thermolysis still.
It has been found that, particularly in the case of continuous thermolysis of a compound of formula III, very high and economically attractive throughputs can be achieved using the process of the invention when a low content of a compound of formula III is maintained in the thermolysates.
Because of the thermal sensitivity of the compound of formula III, difficulties may arise during distillative isolation of the product of formula I. It has been found that a thermolysate having a low content of a compound of formula III can be obtained at high throughputs if the thermolysis is carried out by subjecting the vapors which leave the thermolysis zone to fractionation, and returning the fraction rich in the compound of formula III, optionally after any desired catalyst and/or solvent has been added to the thermolysis zone. In the simplest case, the thermolysis is carried out using a thin-layer evaporator as a reactor, in which case a rectification unit consisting of, for example, bubble-cap trays or packing is present in the vapor line. The reflux of the rectification unit passes into the hot thermolysis zone. Alternatively, the reflux of the rectification unit can be pumped into the receiver of the thermolysis reactor where renewed mixing with the catalyst takes place.
Finally, any compound of formula III remaining in the thermolysate can be converted into thermally stable secondary products by derivatization with suitable derivatizing agents which convert the compound III into a temperature-stable secondary product which can be distilled. Suitable derivatizing agents include organic acids such as acetic acid, anhydrides thereof, higher carboxylic acids, acid chlorides and silylating agents such as trimethylsilyl chloride. A preferred derivatizing agent is acetic anhydride. As a result, even under industrial scale conditions, problem-free isolation of the compounds of formula I by fractional distillation can be achieved.
The present invention is illustrated in greater detail by the following examples, which are not intended to limit the scope of the claims unless otherwise specified.